PROJECTSUMMARY Insomniaisthemostcommonsleepdisorderamongolderadults,affecting50%ofpeopleovertheageof65. Amongthisolderpopulation,sleepdisturbancesareoftenthefirstpresentingsymptomofAlzheimer?sdisease, aswellasotherformsofdementia.ThelinkbetweensleepandAlzheimer?sdiseaseisbidirectional: progressionofdiseaseisassociatedwithworsenedsleep,andpoorsleepcausesworseningcognitive function.Therefore,improvingsleephastherapeuticpotentialinpatientssufferingfromAlzheimer?sdisease. CognitiveBehavioralTherapyforInsomnia(CBT-I)isthefirst-linetherapytotreatsleepdisturbances,but limitedaccessibilityofpractitionersandlongdurationoftherapyarebarriersthatlimitimplementation.Hypnotic medications,a2nd-lineinsomniatreatment,areavoidedinAlzheimer?sdiseasepatientsbecausetheymay exacerbatecognitivedecline.Withwell-validatedmodelsofchronicinsomnia,aging,andAlzheimer?sdisease, anduniquegenetictools,Drosophilaprovidesadynamicsystemtoinvestigatetheunderlyingcellular mechanismsofbehavioralsleepmodification.Idesignedbehavioralparadigmstomodelsleeprestriction,one oftheprimarytenetsofCBT-I,inmutantfliesthatrecapitulatethefeaturesofchronicinsomnia.Sleep restrictioninDrosophilaisachievedbyshorteningthedarkperiodfrom12to4hours,followedbysequential darkperiodexpansionby2hourseveryotherday.Preliminarydatarevealsthataftersleeprestriction,animals exhibitthreefoldincreasesinsleepefficiencyandsleepconsolidation.Thus,thecentralhypothesisofthis proposalisthatbehavioralsleeptherapyaltersactivityofsleeppromotingcenters,allowingformoreefficient andconsolidatedsleep,whichcanbeleveragedtoproducesleepimprovementinagingandAlzheimer?s diseasemodels.Thishypothesiswillbepursuedthrough3specificaims.Aim1willinvestigatehowactivityin sleepcenterschangeswithsleeprestriction,andwhichbrainregionsarenecessaryforimprovementsinsleep. Aim2willelucidatetheeffectsofbehavioralsleepmodificationontheagedbrain.Aim3willanalyzethe changeinbehavioralandmolecularoutcomeswithsleeprestrictioninamodelofAlzheimer?sdisease. Successfulcompletionoftheseaimswillelucidatethecellularmechanismsofbehavioraltherapy,validate sleeprestrictionasatherapeuticstrategyforagingandAlzheimer?sdisease,andserveasafoundationto searchformoleculartargetsthatcanbetranslatedintolong-termtreatmentsforhumanpatients.